Cancer is a multi-faceted disease in which a group of cells display uncontrolled growth, invasion that intrudes upon and destroys adjacent tissues, and sometimes metastasis, or spreading to other locations in the body via lymph or blood. These three malignant properties of cancers differentiate them from benign tumors, which do not invade or metastasize.
There are a number of methods currently used to treat each type of cancer, including surgery, radiotherapy, and chemotherapy. Successful cancer therapy is directed to the primary tumor and to any metastases, whether clinically apparent or microscopic.
The selection of an appropriate treatment is crucial for the patient. It is essential to know when to use immediately a heavy and aggressive treatment protocol in order to prevent extension of an aggressive cancer. In contrast, performing a heavy and aggressive treatment when it is not necessitated by the tumor carried by the patient is also disadvantageous for the patient. Indeed, heavy and aggressive treatments always lead to adverse toxicities that may significantly affect the patient's quality of life. In addition, such heavy and aggressive treatments are usually very costly, and should thus be performed only when it is necessary.
Currently, treatment selection for solid tumors is based on tumor staging, which is usually performed using the Tumor/Node/Metastasis (TNM) test from the American Joint Committee on Cancer (AJCC). The TNM system assigns a number based on three categories. “T” denotes the tumor size, “N” the degree of lymphatic node involvement, and “M” the degree of metastasis. The broader stage of a cancer is usually quoted as a number I, II, III, IV derived from the TNM value grouped by prognosis; a higher number indicates a more advanced cancer and likely a worse outcome.
It is commonly acknowledged that, while this test and staging system provides some valuable information concerning the stage at which solid cancer has been diagnosed in the patient, it is imprecise and insufficient. In particular, it fails to identify the earliest stages of tumor progression. In addition, the TNM test does not give information on the tumor aggressiveness and its usefulness for prognosis is thus limited. Finally, it is limited to solid tumors. Liquid tumors on the other hand are mostly characterized by the identification of cytogenetic alterations.
Several protein and genetic markers have been described in an attempt to refine prognostic information. In particular, gene expression analysis has allowed the identification of multi-gene prognostic signatures. However, the information gathered in different studies have often proven confusing (see e.g. Lenz, Gastrointest Cancer Res, 1(4 Suppl 2): S29-32, 2007; Walther et al., Nat Rev Cancer, 9(7): 489-99, 2009). Overlap between different signatures for the same cancer, for example, can be poor. The robustness of multi-gene signatures is also questionable because they essentially concern cell cycle- or proliferation-associated genes and therefore add nothing to standard clinico-pathological staging. In addition, each signature is limited to a specific type of cancer. None of these markers is thus in routine clinical use.
There is a real need for better prognosis tests of cancer, not only to improve patient global survival, but also to improve their quality of life and to keep aggressive and costly chemotherapies for patients who will really benefit from them. In particular, there is a need for a single-gene prognosis marker which can be used reliably for the prognosis of as many types of cancers as possible.
In normal cell proliferation, DNA replication is performed by 3 DNA polymerases known as replicating polymerases (POLA, POLD and POLE). However, 10 other DNA polymerases have been identified in human cells, which are known as specialized polymerases and which functions are still largely unknown. These specialized polymerases appear to have been maintained through evolution because of their ability to process despite of DNA damage. It also appears that these polymerases are very mutagenic and that their activity is tightly controlled.
POLQ (also known as POL theta or POLθ) is one of these specialized DNA polymerases, and contains a helicase domain in its N-terminal portion and a polymerase domain in its C-terminus. Although the function of this particular specialized DNA polymerase is still largely unknown, it appears to be involved in maintenance of genome stability and in DNA repair (Seki et al., EMBO J, 23: 4484-4494, 2004; Masuda et al., Proc. Natl. Acad. Sci. U.S.A., 102: 13986-13991, 2005, Yoshimura et al., Mol. Cell, 24: 115-125, 2006), but also in the licensing and initiation of DNA replication, probably by facilitating the firing of the replication origins (unpublished data). POLQ expression has been analyzed in various tumors (Kawamura et al., Int J Cancer, 109: 9-16, 2004).
The inventors analyzed the variation of expression of the POLQ gene in tumor versus normal tissues and compared these data with disease progression and clinical features. They showed that POL Q was significantly overexpressed in tumor tissues. In addition, they demonstrated that POLQ deregulated expression contributed actively to tumor progression. Indeed, POLQ overexpression leads to genetic instability and notably DNA damage.